Combination of aneuploidy and high S-phase fraction indicates increased risk of relapse in stage I endometrioid endometrial carcinoma.

INTRODUCTION: Endometrioid endometrial carcinoma is a cancer type with generally excellent prognosis when diagnosed at an early stage, but there is a subset of patients with relapsing disease in spite of early diagnosis and surgical treatment. There is a need to find prognostic markers to identify these patients with increased risk of relapse. Depth of myometrial invasion, histological grade, and presence of lymphovascular invasion are known risk factors. DNA content (ploidy) and proliferation measured as S-phase fraction (SPF) have been discussed as prognostic markers but need additional evaluation. MATERIAL AND METHODS: We evaluated relapse-free survival (RFS) with respect to ploidy and SPF, which was analyzed by flow cytometry on fresh tumor tissue, in a cohort of 1001 women treated for stage I endometrioid endometrial carcinoma in northern Sweden during the period of 1993-2010, with a median follow up time of 12.0 years. Data were obtained from historical records. RESULTS: In simple analysis, both aneuploidy and high SPF were associated to increased risk of relapse with hazard ratios (HR) 2.37 (95% CI 1.52-3.70) and 1.94 (95% CI 1.24-3.02), respectively. Our data also confirmed stage, tumor grade, and ploidy as independent prognostic markers in an age adjusted cox regression multivariable analysis but we did not find SPF to contribute to prognosis. However, the combination of aneuploidy and high SPF identified a group of patients with increased risk of relapse, HR 2.02 (95% CI 1.19-3.44). CONCLUSION: In this study, which is the largest study of ploidy and SPF in stage I endometrioid endometrial carcinoma using fresh frozen tissue, aneuploidy was shown to be an independent prognostic marker. Furthermore, the combination of aneuploidy and high SPF could be used to identify patients with increased risk of relapse.

Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO).

BACKGROUND: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. METHODS: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. RESULTS: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. CONCLUSION: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. TRIAL REGISTRATION: Trial identification number (Clinical Trials.gov): NCT01965080.Nordic Society of Gynecological Oncology: NSGO-EC-0302.EudraCT number: 2004-001103-35.

External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma: a prospective, randomized study--quality-of-life analysis.

BACKGROUND: A combination of vaginal brachytherapy and external beam radiotherapy was compared with brachytherapy alone in medium-risk endometrial carcinomas. Quality-of-life analysis is an important part of a randomized study to find out the optimal adjuvant treatment for this group of patients. OBJECTIVE: To evaluate the value of adjuvant external beam pelvic radiotherapy in adjunct to vaginal brachytherapy in medium-risk endometrial carcinoma. Quality-of-life evaluation is the main topic of this report. METHODS: A consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study end points were locoregional recurrences and overall survival. Secondary end points were recurrence-free survival, toxicity, and quality-of-life. European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 modules were used to evaluate global health status, functional scales, and symptom scales. RESULTS: Five-year locoregional relapse rates were 1.5% after external beam (ERT) plus vaginal irradiation (VBT) and 5% after vaginal irradiation alone (P = 0.013), and 5-year overall survival (OS) rates were 89% and 90%, respectively. External beam radiotherapy was associated with a higher rate of adverse effects from the intestine and the bladder, and quality-of-life parameters deteriorated at the end of radiotherapy but recovered to normal levels within a few months. There was a significant difference in favor of VBT alone with regard to adverse effects of the bowel and urinary tract, and quality-of-life. CONCLUSIONS: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded; but increased late toxicity from the intestine and the bladder. External beam irradiation decreased global health status during and after treatment, and 3 functional scale items (physical, role, and social). Six of 11 symptom items showed a pattern favoring vaginal brachytherapy alone.

External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma--a prospective randomized study.

PURPOSE: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. METHODS AND MATERIALS: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. RESULTS: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. CONCLUSIONS: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.

Phase II study of docetaxel weekly in combination with carboplatin every 3 weeks as first-line chemotherapy in stage IIB to stage IV epithelial ovarian cancer.

OBJECTIVES: The purpose of this study was to assess the response rate, toxicity, progression-free survival, and overall survival in a series of patients with advanced-stage ovarian carcinoma treated with a first-line weekly docetaxel and 3 weekly carboplatin regimen. METHODS: All eligible patients were treated with intravenous docetaxel (30 mg/m) on days 1, 8, and 15, and carboplatin (area under the curve, 5) on day 1; every 21 days for at least 6 cycles. RESULTS: One hundred six patients received at least one cycle of primary chemotherapy (median, 6.0; range, 1-9), and they were evaluable for toxicity assessment. Eighty-five patients had evaluable (measurable) disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% confidence interval, 70.1%-87.5%), and the biochemical response 92.8% (95% confidence interval, 87.2%-98.4%). The median progression-free survival was 12.0 months and the median overall survival was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3 to grade 4 sensory neuropathy. Epiphora, nail changes, and fatigue were frequently recorded nonhematologic adverse effects. CONCLUSIONS: The tolerable hematologic toxicity (no need for colony-stimulating factors) and the low rate of neurotoxicity (only grades 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: neurological toxicity and quality-of-life evaluation.

The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30 mg/m2) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

Decreased hypersensitivity reactions with carboplatin-pegylated liposomal doxorubicin compared to carboplatin-paclitaxel combination: analysis from the GCIG CALYPSO relapsing ovarian cancer trial.

OBJECTIVE: To describe and analyze observed hypersensitivity reactions (HSR) from the randomized, multicenter phase III CALYPSO trial that evaluated the efficacy and safety of the combination of carboplatin and pegylated liposomal doxorubicin (CD) compared with standard carboplatin-paclitaxel (CP) in patients with platinum-sensitive relapsed ovarian cancer (ROC). METHODS: HSR documented within case report forms and SAE reports were specifically analyzed. Analyses were based on the population with allergy of any grade and for grade >2 allergy. RESULTS: Overall 976 patients were recruited to this phase III trial, with toxicity data available for 466 and 502 on the CD and CP arms, respectively. There was a 15.5% HSR rate associated with CD (2.4% grade >2) versus 33.1% with CP (8.8% grade >2), p<0.001. HSRs occurred more often during first cycle in the CD (46%) arm than in the CP arm (16%). Multivariate predictors of allergy were chemotherapy regimen and age; patients randomized to CD and patients ≥ 70 years old on CP had less allergy. Few patients (<6%) stopped treatment due to allergy. Allergy rates were higher in patients who did not receive prior supportive treatment; however there was no relationship between allergy and the type of carboplatin product received, or response rate. CONCLUSIONS: Use of PLD with carboplatin instead of paclitaxel and older age were the only 2 factors predicting a low rate of HSRs in patients with ROC. CD has previously demonstrated superior progression-free survival and therapeutic index than CP. Taken together these data support the use of CD as a safe and effective therapeutic option for platinum-sensitive ROC.

Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study.

OBJECTIVES: To evaluate in a large phase III recurrent ovarian cancer trial (OVA-301): 1) the concordance between CA-125 level vs. best overall response (OR) and progression-free survival (PFS) determined by radiological assessment 2) the impact of early CA-125 changes over the subsequent radiological response, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS. METHODS: Assessment of response in the entire randomized population was performed by the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) and modified Rustin criteria for CA-125 determination. RESULTS: Most CA-125 decreases were observed in RECIST responders (82% of patients treated with the combination and 74% in the PLD alone). CA-125 progression preceded RECIST progression in 35% of patients with a median lead time of 8.4 weeks. A high concordance rate between CA-125 PFS status at 4 months (PFS4) and CA-125 response as a predictor of PFS4 (87%) and radiological response (79%) was found in the combination, with high positive predictive value for radiological PFS4 (92%) and high negative predictive value for OR (90%). An early CA-125 decrease was predictive for the ultimate response since it was found in a high rate of RECIST responders. CONCLUSION: Radiological response was preceded by a favorable predictive CA-125 decrease in a high proportion of patients, suggesting that CA-125 evaluation may be an appropriate tool for tumor assessment in patients with ovarian cancer.

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.

INTRODUCTION: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. METHODS: Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). CONCLUSION: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development.

Communication between mammalian oocytes and their surrounding granulosa cells through the Kit-Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL-Kit-PI3 kinase (PI3K)-Akt-Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3alpha and GSK-3beta, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3alpha and GSK-3beta in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3alpha and GSK-3beta. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit-PI3K-Akt-GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.

Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a.

In recent years, mammalian oocytes have been proposed to have important roles in the orchestration of ovarian follicular development and fertility. To determine whether intra-oocyte Foxo3a, a component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, influences follicular development and female fertility, a transgenic mouse model was generated with constitutively active Foxo3a expressed in oocytes. We found that the female transgenic mice were infertile, which was caused by retarded oocyte growth and follicular development, and anovulation. Further mechanistic studies revealed that the constitutively active Foxo3a in oocytes caused a dramatic reduction in the expression of bone morphogenic protein 15 (Bmp15), connexin 37 and connexin 43, which are important molecules for the establishment of paracrine and gap junction communications in follicles. Foxo3a was also found to facilitate the nuclear localization of p27(kip1) in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth. The results from the current study indicate that Foxo3a is an important intra-oocyte signaling molecule that negatively regulates oocyte growth and follicular development. Our study may therefore give some insight into oocyte-borne genetic aberrations that cause defects in follicular development and anovulation in human diseases, such as premature ovarian failure.

Control of mammalian oocyte growth and early follicular development by the oocyte PI3 kinase pathway: new roles for an old timer.

A large amount of information has accumulated over the past decade on how gonadotropins, steroid hormones and growth factors regulate development of the mammalian ovarian follicle. Moreover, the bi-directional communication between mammalian oocytes and their surrounding somatic (granulosa) cells has also been shown to be crucial for this process. The intra-ovarian factors, or more specifically, the intra-oocyte signaling pathways that control oocyte growth and early follicular development are largely unknown, however. Based on both in vitro studies and in vivo functional studies using gene-modified mouse models, this review focuses on the key features of the phosphatidylinositol 3 kinase (PI3K) pathway in growing mouse oocytes and on the novel functions of the oocyte PI3K pathway in controlling mammalian oocyte growth and follicular development that have come to light only recently. We propose that the PI3K pathway in the oocyte, which is activated by granulosa cell-produced Kit ligand (KL) via the oocyte-surface receptor Kit, may serve as an intra-oocyte network that regulates both oocyte growth and the early development of ovarian follicles.

Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells.

E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.

Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development.

Although communications between mammalian oocytes and their surrounding granulosa cells mediated by the Kit-Kit ligand (KL, or stem cell factor, SCF) system have been proven to be crucial for follicular development, Kit downstream signaling pathways in mammalian oocytes are largely unknown. In this study, by using ovaries and isolated oocytes from postnatal mice and rats, we demonstrated for the first time that components of the PI3 kinase pathway, the serine/threonine kinase Akt (PKB) which enhances cellular proliferation and survival, and an Akt substrate FKHRL1 which is a transcription factor that leads to apoptosis and cell cycle arrest, are expressed in mammalian oocytes. By using an in vitro oocytes culture system, we found that oocytes-derived Akt and FKHRL1 are regulated by SCF. Treatment of cultured oocytes with SCF cannot only rapidly phosphorylate and activate Akt, but also simultaneously phosphorylate and may therefore functionally suppress FKHRL1, through the action of PI3 kinase. Together with our in situ hybridization and immunohistochemistry data that Akt and FKHRL1 are mostly expressed in oocytes in primordial and primary ovaries and reports that FKHRL1 gene-deficient mice exhibited excessive activation from primordial to primary follicles as well as enlarged oocyte sizes, we suppose that in mammalian oocytes, actions of granulosa cell derived SCF on primordial to primary follicle transition and subsequent follicle development may involve activation of Akt and inhibition of FKHRL1 activities in oocytes. The role of oocyte's Akt may be to enhance follicle development and the role of oocyte's FKHRL1 may be to inhibit follicle development. We propose that the cascade from granulosa cell SCF to oocyte Kit-PI3 kinase-Akt-FKHRL1 may play an important role to regulate the growth rate of mammalian oocytes and hypothetically also the oocyte secretion of factors that may regulate the activation and early development of ovarian follicles.

A systematic overview of radiation therapy effects in cervical cancer (cervix uteri).

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn. There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer. There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer. The NCI has recently published an announcement stating that cisplatin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages ( >IIB). There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea. There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer. There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.

A systematic overview of radiation therapy effects in uterine cancer (corpus uteri).

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for uterine cancer is based on data from one randomized study. Moreover, data from two prospective studies and seven retrospective studies were used. In total, 10 scientific articles are included, involving 3,446 patients. The results were compared with those of a similar overview from 1996 including 13 597 patients. The conclusions reached can be summarized as: There is fairly good evidence that there is no need for adjuvant radiotherapy in patients with good risk uterine cancer. There is fairly good evidence that adjuvant radiotherapy reduces the relapse rate in high-risk patients but has no impact on survival. There is substantial documentation showing that medically inoperable patients and patients with locally recurrent uterine cancer can be treated with radiotherapy alone with curative effect.

A systematic overview of radiation therapy effects in ovarian cancer.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for ovarian cancer is based on data from six randomized trials. Moreover, data from one prospective study and three retrospective studies were used. In total, 10 scientific articles are included, involving 1 282 patients. The results were compared with those of a similar overview from 1996 including 15042 patients. The conclusions reached can be summarized in the following points: There is no scientific documentation supporting adjuvant radiotherapy for early-stage, low-risk patients. No studies have been reported where adjuvant radiotherapy has been compared with no adjuvant therapy in early-stage, high-risk patients. Adjuvant radiotherapy, either whole abdominal irradiation or intraperitoneal p32, has been compared with adjuvant chemotherapy in early-stage, high-risk patients. There is no scientific evidence to show that there is a difference in efficacy. There is some evidence to suggest that adjuvant radiotherapy after radical surgery leads to an increase in disease-free survival rate for patients with advanced-stage ovarian cancer. There is little documentation on long-term side effects (second malignancy) after adjuvant radiotherapy and no conclusions can be drawn.

Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum.

The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B). and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m2/week in the weekly arm, and 72.7 mg/m2/week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m2/week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids.